Yeah. I went there. Since everyone from Motley Fool to MassDevice to the Wall Street Journal feels the need to use "Stent Wars" (a pun that I originated on this website a decade ago) I've decided to go all TV. Actually, "The Next Generation" is also a more appropriate reference than the "Wars" moniker, because the story here is no longer so much about behemoth entities and dark lords battling each other for control of the universe (not that this aspect has gone away) but a story of refinement, sleeker technology and, yes, much more Data! And this past couple of weeks has seen some important developments in the next generation of stents that are positive for both patients and physicians.

For those who missed the first generation, a quick recap of the original series follows (I like to call it "putting things in perspective"). But for those who know all about "late stent thrombosis", you can just skip to the new episodes.

By 2004, the U.S. FDA had approved two drug-eluting stents: Cypher and then Taxus. In the previous decade, bare metal stents had vastly improved on the 30-40% restenosis seen with plain old balloon angioplasty (POBA) but 20-25% of these stents continued to close up with excess tissue growing over the metal struts. Coating these stents with a drug, released from a plastic polymer, inhibited this tissue growth and restenosis rates were halved.

But a problem arose -- sometimes tissue growth was too inhibited, the metal struts did not get fully covered and the artery wall never "healed" completely, even after one or more years. In some cases, blood platelets gathered in these areas and caused a clot, known as late stent thrombosis (LST) -- not common but fatal 30-40% of the time.

LST was a relatively low occurrence event, maybe one or two patients out of a hundred, and rare enough not to be picked up in the clinical trials that were used to gain approval for these devices, trials that enrolled maybe 1,000 patients with single vessel discrete disease -- stable patients and relatively simple straight-forward blockages -- and not followed up beyond one year. These were the "on-label" patients. But almost half of the PCIs were being done "off-label" -- in more complex situations than the patient cohorts in the clinical trials. And "off-label" didn't mean "bad" because many of these complex patients benefitted tremendously from the interventional therapy. "Off-label" just meant that a large clinical trial testing this therapy for this type of patient had not been done. FYI, the use of Plavix (clopidogrel) after stent placement is also technically "off-label", yet every stent patient is required to take Plavix. For more on this, read my 2006 blog post, "The Catch-22 of Plavix and the FDA: Not My Job."

2006: A Turning Point
Reports of these late stent thrombosis events (primarily from Europe where DES had been in use longer) generated a firestorm, culminating in a two-day FDA Stent Safety hearing in December 2006. One after another, cardiologists from the U.S., Sweden, Italy et al and grim-faced device executives from Cordis/J&J and Boston Scientific reported data, studies, parsed outcomes from the existing clinical trials. The panel, plus invited guests, Drs. Steve Nissen, Eric Topol, et al, listened, questioned and shook their heads at the lack of data that existed about these late events.

I remember the panel chair, Dr. William Maisel, grilling executives from Cordis/J&J about why they hadn't continued to follow-up patients past the one year mark. "I find it extremely concerning that we don't have any registry data from Cordis out past 1 year," he complained.

The result of those hearings: a recommendation to extend Plavix and aspirin for at least one year, although as pretty much everyone opined, there was a dearth of evidence as to whether this was or was not necessary or beneficial.

It certainly wasn't beneficial to the stent manufacturers. Drug-eluting stent usage dropped from 90% to the low 60s over the next six months, over concerns about late stent thrombosis and the results of the COURAGE trial only three months later. But that's another story.

The Next Generation
But change was already in the works. At those same 2006 FDA stent hearings, the panel also heard from Medtronic and Abbott executives about the next generation of DES, and trials that were far more comprehensive. Panel member Dr. John Somberg, referencing the Endeavor program from Medtronic, stated:

"I was extremely reassured by hearing from a company that's well along in its process -- I heard numbers like 5,000 and 10,000 patients to 5 years follow-up, and I think that is to be commended very highly. So maybe industry's way ahead of this committee anyway."

And this past month has borne out the promise. Two weeks ago, the FDA approved Medtronic's new Resolute Integrity™ Drug-Eluting Stent with a specific on-label indication for use in diabetic patients. Why? Because the company looked at over 5,000 patients with multi-year follow-up, and the results, a 7.8% event rate in diabetics, almost halved the current standard of performance. And the rates of late stent thrombosis for the new generation of DES has been reduced significantly, in some studies (like the TWENTE trial or the RESOLUTE US) to almost zero.

More robust data from larger and longer-term studies has shown increased performance from these devices, better and safer outcomes for patients. In fact the adverse event rates in this "new generation" are so low that Dr. David Kandzari of Piedmont Heart Institute in Atlanta recently commented to TCTMD:

"...we have reached a point where the [adverse event] outcomes now are so low and so favorable and so similar across everolimus-eluting stents and stents like Resolute that it would be very difficult for newer stents to demonstrate superiority.... [Commenting on a stent thrombosis rate in the RESOLUTE trial of only 2 in 1,402 patients at one-year] To show superiority over a rate like that would be virtually impossible."